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Management of Thyroid Disorders:
A Case Bases Approach
James Voirin, DO FAAFP Physician Associates LLC
Orlando, FL
Best Practices Pearls
Have a low threshold to test for thyroid disease
Treatment of both subclinical and overt disease should be individualized and monitored
Manage issues around variable therapeutic equivalence of levothyroxine products
Appropriately counsel, screen, and monitor thyroid function in pregnancy to improve outcomes
Case Study: Grace
Grace is a 43 year old WF with a swelling in her neck for ~6 weeks. She has noticed a recent onset of myalgias, fatigue, hair loss, weight gain, and dry skin. She also noticed thinning of the lateral third of her eyebrows. Past medical history is remarkable for hyperlipidemia.
Case Study: Grace
Physical Exam
Height: 5’7”
Weight: 160 lbs
BMI: 25.1
BP 132/84 P 76
Thyroid smooth, diffusely, enlarged, non-tender
TSH 7.45 (0.5-4.5) Free T4: 1.2 (0.8-1.8)
Case Study: Grace
Is the patient hypothyroid?
Are additional tests necessary?
Should she be treated with thyroxine?
If treatment is initiated, what dose should be initiated?
What are the potential benefits of treatment?
Physiology
Definitions and Diagnosis
Definitions and Diagnosis Underactive
Hypothyroidism
Primary: high serum thyrotropin (TSH) and a low serum free thyroxine (FT4)
Secondary and Tertiary (central): low FT4 and TSH not elevated
Subclinical Hypothyroidism
Only an elevated TSH with a normal FT4 level
Both overt and subclinical disease can be symptomatic
McDermott MT, et al. J Clin Endocrinol Metab. 2001;86:4585-4590.
Prevalence
Prevalence
NHANES III: 13,344 people (54% female) without known thyroid disease had TSH, T4, thyroglobulin antibodies, and thyroid peroxidase antibodies measured
Hypothyroidism in 4.6% (0.3% overt and 4.3% subclinical)
Hyperthyroidism was found in 1.3% (0.5% overt and 0.7% subclinical)
Serum thyroid peroxidase antibody concentrations elevated in 11%
Hollowell JG, et al. J Clin Endocrinol Metab. 2002;87:489-499
Higher Prevalence in 70-79 Year-Olds
3 to 8 times more common in women than men
Mean TSH is lower in blacks than whites or Hispanics
Mean TSH rises as we age
Hyperthyroidism and Hypothyroidism Study Results
Hyperthyroidism Hypothyroidism
Black women 9.7% 6.2%
White women 6.0% 16.5%
Black men 3.2% 1.7%
White men 2.2% 5.6%
Golden SH, et al. J Clin Endocrinol Metab. 2009;94:1853-1878.
Etiology
Hashimoto’s Thyroiditis (Chronic Lymphocytic Thyroiditis)
Most common in USA
Historic Note: 1st discovered Auto-Immune Disorder
Diagnosed with antithyroid peroxidase (antiTPO) antibodies or antimicrosomal antibodies (AMA)
Post Treatment Graves’ Disease
No function after radiation or surgery
Iodine Deficiency
Most common worldwide associated with a goiter
Rare in North America, but (?) re-emergence with “natural” salt
Hypothalamic-pituitary Disease (secondary or central)
Etiology of Hypothyroidism
Golden SH, et al. J Clin Endocrinol Metab. 2009;94:1853-1878. Hollowell JG, et al. J ClinEndocrinolMetab. 1998;83:3401-3408.
Hypothyroidism Symptoms
Hypothyroidism and Subclinical Hypothyroidism Signs & Symptoms
Fatigue Memory and mental impairment
Weight gain from fluid retention (but usually not morbid
obesity)
Decreased concentration
Dry skin and cold intolerance Depression
Yellow skin Irregular or heavy menses and infertility
Coarseness or loss of hair Myalgias
Hoarseness Hyperlipidemia
Goiter Macrocytic anemia
Reflex delay, relaxation phase Bradycardia and hypothermia
Ataxia Myxedema fluid infiltration of tissues
Constipation Carpal Tunnel Syndrome
Sir William Osler
Listen to the patient. They
are telling you the diagnosis
Walked into muggy ward when the yet to be examined new patient was not in her bed
Asked the students: “Where is the hypothyroid patient?”
How did he diagnose the unseen, unmet patient?
The Model for Sherlock Holmes?
Sir William Osler
Listen to the patient. They
are telling you the diagnosis
Walked into muggy ward when the yet to be examined new patient was not in her bed
Asked the students: “Where is the hypothyroid patient?”
How did he diagnose the unseen, unmet patient?
Extra Blankets
Bed undisturbed
Hairs and flaked skin on the pillows
Clothes suggested obesity
The Model for Sherlock Holmes? Elementary, my dear Watson…
Hypothyroidism Work-Up
History
Radiation and Surgery
Infections
TB, Pneumocystis carinii
Infiltrative Disease
Riedel’s, leukemia, scleroderma, hemochromatosis
Meds
Lithium
Prednisone
Metformin
Androgens and Anabolic Steroids
Heparin
Tyrosine Kinase Inhibitors
Interferon, Interleukin
Amiodarone (3mg per 100mg)
Pre and Post Treatment
Physical +/- Goiter
Slowed movement and speech
Hoarse voice
Bradycardia
Carotenemia
Hung deep tendon reflex
Coarse skin
Puffy eyes and face
Enlarged tongue
Galactorrhea
Diastolic Hypertension
Hypothyroidism Work-Up
Work-Up
Lab
TSH, FT4
No need to check thyroid antibodies
CBC, CMP, lipids
Imaging
No need for thyroid imaging unless abnormal palpations or pain
No need of pituitary MRI unless signs of central hypothyroidism (<1%)
Hypothyroidism Work-Up
Decision to treat subclinical disease is controversial and should be individualized
Recommended if TSH > 10 or patient is symptomatic
Individual decision when no symptoms of TSH only slightly elevated
Levothyroxine (LT4) is the recommended replacement
Average replacement dose is 112 mcg/daily or 1.6 mcg/Kg/day
Controversy Hypothyroidism and Subclinical Hypothyroidism
In some older patients and those with CAD start at 25 or 50 mcg as T4 increases myocardial 02 demands and risk of angina and arrhythmia
Take on empty stomach (ideally 1 hour before breakfast)
Coffee, antacids, and calcium interfere with absorption
Special Cases and Considerations Hypothyroidism and Subclinical Hypothyroidism
CAD, coronary artery disease
Patients may feel better as soon as two weeks, but it can take months
Changes are often incremental, not dramatic
Takes 6 weeks to see blood levels change
FT4 rises first, TSH is slower to fall
Recheck FT4 and TSH at 6 weeks
If still sub-therapeutic, increase by 12.5 or 25 mcg, and recheck every 6 weeks
Once stable, check every 6 months for first year, then annually
Hypothyroidism and Subclinical Hypothyroidism
The thyroid produces both T3 and T4
LT4 therapy has no T3
Patients on T4 alone have higher than normal
T4/T3 ratios
Peripheral conversion of T4 to T3 may be inadequate in some patients → tissues have deficient T3 level
So is T4 monotherapy = “Tissue hypothyroidism”
BUT T3 has short half life, may need extended release
Data doesn’t support use of T3 or desiccated thyroid
Controversy T3 and “Natural” Therapy
Arguments PRO and CON for T3 Supplementation
N Eng J Med 1999
Mood better with T3: 7 of 8 tests P<0.04
No difference in:
Neuropsychological tests
BP and serum lipids
Eur J Endocrinol 2009
49% preferred combination of T4 and T3; 15% T3 alone; 36% had no preference
Controversy T3 and “Natural” Therapy
Bunevicius R, et al. NEJM. 1999;340:424-429. WiersingaWM. EurJ Endocrinol. 2009;161:955-959.
But no benefit demonstrated in over nine studies1
Meta-analysis of >1,200 patients randomized to LT4 monotherapy2 or combination therapy with T3 showed no difference in body pain, depression, lipids, anxiety, fatigue, quality of life, body weight
Controversy T3 and “Natural” Therapy
1Levitt A, et al. T4 plus T3 treatment for hypothyroidism: a double-blind comparison with usual T4. 74thAnnual Mtg of the American Thyroid Association. Los Angeles, CA, Oct 10, 2002; Walsh JP, et al. J ClinEndocrinolMetab. 2003;88:4543-4350; SawkaAM, et al. J ClinEndo Metab. 2003; 88:4551-4555; CassioA, et al. Pediatrics. 2003;111:1055-1060; Clyde PW, et al. JAMA. 2003; 290:2952-2958; SiegmundW, et al. ClinEndocrinol(Oxf). 2004;60:750-757; SaravananP, et al. J ClinEndo Metab. 2005;90:805-812; AppelhofBC, et al. J ClinEndo Metab. 2005;90:2666-2674; Escobar-MorrealeHF, et al. Ann IntMed. 2005;142:412-424; Ma C, et al. NuclMed Commun. 2009;30:586-593. 2Grozinsky-GlasbergS, et al. J Clin Endocrinol Metab. 2006;91:2592-2599.
1891: Dr. George Murray 1st used sheep thyroid extract to successfully treat his patient with myxedema for 28 years
Same issues with naturally desiccated thyroid or NDT (a mixture of T3 and T4 made from porcine or beef thyroid glands) as with T3
Must use TSH for monitoring
NDT contains all thyroid hormones: T4, T3, T2, T1,, and calcitonin which is present in natural thyroid and usually lacking after total thyroidectomy, which removes the parathyroid glands
Synthetic T4 alone is the recommended therapy by AACE as there is no proven evidence of benefit with NDT
Daily dose of 100 µg of LT4 = biologic activity to 101 mg of NDT
Controversy T3 and “Natural” Therapy
Sawin CT, et al. Metabolism. 1978;27:1518-1525.
Protein Binding
Thyroid hormone is highly protein-bound, so changes in the amount of binding protein and drugs that compete for binding change the amount of active free thyroid hormone
The thyroid replacement dosage must be changed in response to altercations in binding status
HIGHT BINDING: High estrogen states (pregnancy, oral contraceptive use, or postmenopausal estrogen replacement), so the dose of LT4 must be increased
LOW BINDING: Low androgens, nephrosis, protein-losing enteropathies, cirrhosis, and aging may decrease levels of thyroid binding proteins, and so require a reduced dose
Drug Interactions Multiple Complex Mechanisms of Actions
Iodine and iodine-containing drugs such as radiographic contrast (may cause both hypothyroidism and hyperthyroidism weeks later)
Lithium (therapeutic levels cause thyroid enlargement in half the patients and hypothyroidism in 20%, but may also cause hyperthyroidism)
Oral tyrosine kinase inhibitors (blocks clearance)
Proton pump inhibitors
Concomitant use of calcium, iron, and bile acid sequestrates
Selective estrogen receptor modulators (SERMs), anabolic steroids, and glucocorticoids (decrease protein binding so dose may need to be reduced)
Amiodarone (multiple causes for both hypothyroidism and hyperthyroidism)
Phenobarbital, rifampin, phenytoin, and carbamazepine (increase the metabolism of both T4 and T3 so patients on T4 supplementation may need higher dosages)
Beta adrenergic antagonists including high-dose propranolol (inhibit T3 production)
NSAIDs including salicylates, heparin, and furosemide (decrease T4 binding)
Dopamine (suppresses TSH)
Drug Interactions Multiple Complex Mechanisms of Actions
Is the patient Hypothyroid?
Elevated TSH and normal T4 is consistent with subclinical hypothyroidism
Are additional tests necessary?
TPO antibodies could be ordered but are not necessary for treatment
Should she be treated with thyroxine?
The patient has symptoms of fatigue, weight gain, hyperlipidemia
If treatment is initiated, what dose should be started?
May start with 5-50 mcg per day, although full dose replacement could be used. TSH should be repeated in 5-6 weeks
Case 1 Answers
Thyroid Preparation
Levothyroxine-T4 *Preferred Therapy*
Liothyronine-T3 (Cytomel)
Liotrix-4:1 mixture T4 and T3 (Thyrolar)
Thyroid USP-Dessicated thyroid extract (Armor Thyroid)
Jonathan is a 66 year old African-American male with a history of palpitations, fatigue, and tremor. He has a history of coronary artery disease and hyperlipidemia.
Case Study: Jonathan
Case Study: Jonathan
Physical Exam and Lab Findings
Height: 5’7”
Weight: 188 lbs
BMI: 29.4
BP 142/72 P 112
TSH <0.1 Free T4 and T3 wnl
Temp 97.8F
PE normal except for fine tremor of hands
Case Study: Jonathan
Is the patient hyperthyroid?
Are additional tests necessary?
If indicated, what treatment is necessary?
What are the potential benefits of treatment?
Hyperthyroidism Usually excess production of free thyroid hormones (either T3
or T4 or both) in serum with suppressed HS-TSH or highly sensitive (3rd generation) TSH (<0.01mU/L)
Thyrotoxicosis includes hyperthyroidism but also excess release of hormone in thyroiditis or excess exogenous T4
Subclinical Hyperthyroidism (SH) Low of undetectable (HS-TSH) but normal range for both
triiodothyronine (T3) and free thyroxine (FT4)
Both overt and sub-clinical disease may lead to characteristic signs and symptoms
McDermott MT, et al. J Clin Endocrinol Metab. 2001;86:4585-4590.
Definitions and Diagnosis Overactive
Etiology of Hyperthyroidism
Graves’ Disease
Most common
Auto-immune: long acting thyroid stimulating antibodies (LATS)
Thyroid Nodules
“Toxic: nodules (becoming autonomous)
Benign or malignant, single or multiple
Toxic nodular goiter- most common cause in the elderly
Brent GA. N Engl J Med.2008;358:2594-2605.
Excessive Thyroid Supplementation
Iatrogenic
Exogenous
Thyroiditis (excessive release, not production)
Early Hashimoto’s, radiation, palpation,
post partum
Rare Causes: pituitary adenoma,
teratomas
Etiology of Hyperthyroidism
Brent GA. N Engl J Med.2008;358:2594-2605.
Etiology of Subclinical Hyperthyroidism Exogenous
10 million Americans and 200 million worldwide take thyroid hormone
All are at risk for subclinical hyperthyroidism, whether intentional or unintentional
In patients on LT4 (levothyroxine), up to 25% may have low TSH
Associated with lower bone density
Associated with atrial fibrillation
BUT subclinical hyperthyroidism is the goal of thyroid hormone therapy in thyroid cancer, in some thyroid nodules, multinodular or diffuse goiters, or a history of head and neck irradiation
Symptoms
Hyperthyroid Symptoms
Overt Hyperthyroidism and Subclinical Hyperthyroidism Signs & Symptoms
Nervousness and irritability Exertional intolerance and dyspnea
Palpitations and tachycardia Menstrual disturbance (decreased flow)
Heat intolerance or increased sweating Impaired fertility
Tremor Mental disturbances (anxiety)
Weight loss Sleep disturbances (including insomnia)
Alterations in appetite Changes in vision, photophobia, eye irritation, diplopia, or
exophthalmos (with Graves’ disease)
Frequent bowel movements or diarrhea Fatigue and muscle weakness
Dependent lower extremity edema Thyroid enlargement (depending on cause)
Sudden paralysis Pretibial myxedema (in patients with Graves’ disease)
Hyperthyroidism Work-Up
History
Thyroiditis including trauma
Meds
Amiodarone
Iodine
Physical
Hyperactivity and rapid speech
Stare (lid retraction) and lid lag
Sweaty
Fine hair
Tachycardia and Atrial Fibrillation
Hypertension
Hyperreflexia
Muscle weakness
Tremor
Thyroid
Size, nodularity, tenderness
Hyperthyroidism Work-Up
Lab
3rd generation
TSH (<0.05 mU/L)
T4 (RIA), FT4,
T3 (RIA), FT3
CBC, CMP including alkaline phosphatase
Imaging
Radioiodine uptake and scan
If high, increased production such as Graves’ or nodule(s)
If low, thyroiditis or source is outside of thyroid (struma ovarii or exogenous)
Radioiodine Scan
Treatment
Graves’ Disease Treatment Two Step Process
>95% satisfaction with all three therapy choices, but relapse risk higher with med
1st STEP: Rapid amelioration of symptoms with a beta blocker
Palpitations, tachycardia, anxiety, tremor, heat intolerances
2nd STEP: Decreasing thyroid hormone synthesis
1.) Thionamide
Methimazole and propylthiouracil (PTU)
Inhibit the enzyme thyroid peroxidase
3-8 weeks to work, often a step before permanent ablation, but may be well tolerated long term, 37% relapse
2.) Radioiodine
60% of endocrinologists prefer to treat with a capsule of I131
6-18 weeks to work, worsening of Graves’ ophthalmopathy, 21% relapse
3.) Surgery
1% use, lowest relapse (6%(, surgical risk (recurrent laryngeal nerve injury)
Obstructive goiter or suspicious nodule, ophthalmopathy, contraindications to meds or radioiodine
Anatomy Review
In 1866, Samuel David Gross said, "If a surgeon should be so foolhardy as to undertake it [thyroidectomy] … every step of the way will be environed with difficulty, every stroke of his knife will be followed by a torrent of blood, and lucky will it be for him if his victim lives long enough to enable him to finish his horrid butchery."
Controversy Subclinical Hyperthyroidism Treatment
Treat as high risk patient
>65 years old
Heart disease
Osteoporosis
Treat as low risk if TSH value is
<0.1 mU/mL
Same treatment options as in Graves’
Faber J, et al. Eur J Endocrinol. 2001;145:391-396. Mudde AH, et al. Clin Endocrinol. (Oxf) 1994; 41:421-424. Faber J, et al. Clin Endocrinol. (Oxf) 1998;48:285-290.
Is the patient hyperthyroid?
TSH low with normal T3 and T4 indicating subclinical hyperthyroidism
Are additional tests necessary?
Yes, thyroid uptake scan, CBC, CMP
Thyroid scan consistent for autonomous functioning adenoma
If indicated, what treatment is necessary? Same as for hyperthyroidism
Clinical Questions Case 2
Autonomous thyroid nodule: Appearance on thyroid scintigraphy
UptoDate 2016
What are the potential benefits of treatment?
Treatment indicated to prevent Atrial fibrillation and osteoporosis
Clinical Questions Case 2
Normal TSH (0.4-4)
70yo (5.9-7.5)
> 90yo (6.5-7)
UptoDate 2016
Clinical Considerations: Age adjusted TSH
Pregnancy
Pregnancy
Maternal and fetal hypothyroidism associated with risks to fetal neural development
Maternal hypothyroidism at increased risk for anemia, myopathy, congestive heart failure, preeclampsia, placental abnormalities, low birth weight, and postpartum hemorrhage
Maternal thyrotoxicosis is associated with fetal tachycardia, fetal hyperthyroidism, small for gestational-age babies, prematurity, preeclampsia, and stillbirths
Huang SA, et al. J Clin Endocrinol Metab. 2003;88:1384-1388. Kester MH, et al. J Clin Endocrinol Metab. 2004;89:3117-3128.
Pregnancy is a “Thyroid Stress Test”
Thyroid increases 10% to 15% during pregnancy in patients who live in countries with adequate iodine, and by 20% to 40% where there is an iodine deficiency
T4 and T3 production increases by 50%
The daily iodine requirement goes up by 50% due > T4 production and > renal clearance
WHO recommends 250 mcg of iodine daily
TSH drops the most in the first trimester under the impact of placental human chorionic gonadotropin (hCG), which itself has a weak thyrotropic effect → possible transient
hyperthyroidism
Thyroid Binding Globulin (TBG) inceases
Huang SA, et al. J Clin Endocrinol Metab. 2003;88:1384-1388. Kester MH, et al. J Clin Endocrinol Metab. 2004;89:3117-3128. Abalovich M, et al. J Clin Endocrinol Metab. 2007;92(8 Suppl);S1-S47.
Controversy Screening
American Thyroid Association, American College of Obstetricians and Gynecologists, and The Endocrine Society all recommend targeted rather than universal screening
BUT may miss 1/3 of pregnancies with hypothyroidism
Screening for Thyroid Disease
Suggested indicators for targeted thyroid case finding in pregnancy, where the incidence of clinical hypothyroid
disease is high and benefit of therapy is clear, women with:
A history of hyperthyroid or hypothyroid disease,
postpartum thyroiditis, or thyroid lobectomy
Type 1 diabetes
A family history of thyroid disease Other autoimmune disorders
A goiter Infertility should have screening with TSH as part of their
infertility work-up
Thyroid antibodies (when known) Prior therapeutic head or neck irradiation
Symptoms or clinical signs suggestive of thyroid under
function
A prior history of preterm delivery
The following conditions screening may be considered since the incidence might be high enough but no known
benefit of treatment has yet been determined:
Women in whom the last delivery was preterm Women with recurrent pregnancy loss
Abalovich M, et al. J Clin Endocrinol Metab. 2007;92(8 Suppl);S1-S47.
Lab Findings
Lab should provide pregnancy and trimester specific ranges of all thyroid tests
If not provided, then for TSH use:
1.) First trimester 0.1 to 2.5
2.) Second trimester 0.2 to 3.0
3.) Third trimester 0.3 to 3.0
TBG is higher so total T4 is higher as total T4 reflects the increased protein binding in pregnancy
FT4 however is more likely to be normal but can be technically difficult to accurately measure
Ain KB, et al. J Clin Endocrinol Metab. 1987;65:689-696. Ballabio M, et al. J Clin Endocrinol Metab. 1991;73:824-831. Glinoer D. Endocr Rev. 1997;18:404-433. Lee RH, et al. Am J Obstet Gynecol.2009;200:260.e1-e6. Soldin OP, et al. Thyroid. 2004;14:1084-1090.
Hyperthyroidism
hCG-mediated hyperthyroidism is usually transient and does not require treatment
PTU is 1st choice and ATA recommends treatment saying benefits > risks, but is category 4
Surgery if PTU is contraindicated
Controversy Management Consult an
Experienced Endocrinologist
PTU, propylthiouracil
Subclinical Hypothyroidism
Lower pregnancy risk than with overt disease
RX with LT4 may improve baby’s neuro development
The Thyroid Dysfunction during Pregnancy and Postpartum Guideline Task Force recommends treatment
Elevated antithyroid peroxidase antibody
(TBO antibodies) in euthyroid pregnant patients
Increased risk of fetal loss, perinatal mortality, and large-for-gestational-age
High risk to become hypothyroid, so need monitoring
LT4 may lower miscarriage rates
ATA does not recommend for or against treatment
Controversy Management Consult an
Experienced Endocrinologist
Best Practices Pearls
Have a low threshold to test for thyroid disease
Treatment of both subclinical and overt disease should be individualized and monitored
Manage issues around variable therapeutic equivalence of levothyroxine products
Appropriately counsel, screen, and monitor thyroid function in pregnancy to improve outcomes
The End!